Biology subjects

Duncan, C.

Publications and source records attributed to Duncan, C..

6 recordsLinked to original sources

bioRxiv2026

Arsenic Impairs Critical Cellular Events of Human Cardiac Development Across Differentiation and Metabolic Maturation

Arsenic (As) is a widespread environmental contaminant, with exposure occurring primarily through contaminated food and water or cigarette smoke. Maternal exposure to As represents a significant risk factor for congenital heart disease in offspring. However, the mechanisms underlying As induced developmental cardiotoxicity remain poorly defined. Pluripotent stem cells provide an excellent platform for studying mechanisms of developmental toxicity. Embryoid bodies (EBs) derived from stem cells, can recapitulate many key events of early embryogenesis including germ layers specification. Human cardiomyocytes are derived from mesodermal progenitors. NKX2.5 governs cardiac specification and morphogenesis, and its mutation produces atrial and ventricular defects in humans. Using an NKX2.5 reporter stem cell line, we modeled mesoderm differentiation in EBs and cardiac induction in a 2D cardiomyocyte differentiation system. In an 8 day differentiation protocol, As (0.05 M; 3.75 ppb) significantly suppressed cardiomyocyte differentiation and cardiac induction. However, As increased mesodermal markers (HAND1, SNAI2, HOPX) gene expression. In contrast, cardiac specific genes, including NKX2.5, GATA4, Troponin T, and alpha actinin, were markedly downregulated in the presence of As. As also reduced expression of genes related to cardiac induction, fibroblast function, and vascular markers in the cardiac organoid model. As impaired cardiomyocyte maturation related gene expressions at concentrations without affecting cardiomyocyte proliferation. In a zebrafish model of early heart development, As increased heart rate and disrupted ion channel gene expression. In conclusion, As inhibits ESC differentiation into cardiomyocytes and disrupts cardiomyocyte maturation. Combining stem cell derived models with zebrafish exposure, this study illuminates adverse outcome pathways for As induced congenital heart defect.

pharmacology and toxicology↗

bioRxiv2025

The bind of the burrow: space use is dominated by selection for burrow habitat over foraging habitat in an arid-adapted carnivore

Our understanding of habitat selection in wild vertebrates has been heavily influenced by observations of preferred foraging areas. However, foraging is only one of many ways animals interact with their environment, and preferences for habitat features that support resting, breeding, and safety, along with trade-offs between these needs, remain underexplored. These trade-offs are likely to be particularly acute in complex environments where these needs are met in different locations. Using a long-term dataset of movements and life history, we examine how preferences for foraging areas and burrow sites shape space use in Kalahari meerkats (Suricata suricatta). Meerkats cannot dig new sleeping and breeding burrows and must use those abandoned by other species, potentially generating trade-offs in daily space use if overnight refuges are far from optimal foraging areas. We find that space use is strongly anchored by burrow location, with burrows in calcareous pans and dry riverbed ("white sand") habitat being preferred year-round and showing lower burrow switching rates. However, white sand areas were not preferred for foraging, and yielded lower weight gains, particularly during the dry season. As a result, meerkats faced a trade-off between optimal burrow locations and productive foraging grounds, as indicated by faster, longer, and more energetically costly travel when moving through or waking up in white sands. Our results suggest that changes in the distribution or abundance of key burrow-constructing species in desert environments may have cascading effects on the many secondary burrow-using species that depend on them for survival and reproduction. More broadly, our results highlight that limited refuge availability across the landscape can impose strong ecological constraints on animals and may restrict behavioural plasticity under environmental change, particularly if productive foraging areas shift.

ecology↗

bioRxiv2025

Dyr726, a brain-penetrant inhibitor of PI3Kα, Type III receptor tyrosine kinases, and WNT signalling

The vast majority of clinical small molecule multi-kinase inhibitors (mKI) report abject failures in targeting cancers with high stem cell contents like high-grade glioma and colorectal cancers. The FDA-approved mKIs to date ablate receptor tyrosine kinase signaling but do not target the paradoxical WNT signaling which is a key survival driver for the self-renewing cancer stem cells. The WNT pathway enhances cancer plasticity and triggers relapse of highly heterogenous tumours. Using de novo synthesis and structure-activity-relationship (SAR) studies with blood-brain-barrier (BBB) penetrant mKI scaffolds, we designed a highly potent and selective small molecule inhibitor of PI3K, PDGFR/KIT, and the WNT pathway denoted Dyr726. Dyr726 is superior to clinical mKIs and inhibits PI3K-AKT-mTOR and WNT-pathway signaling at multiple nodes thereby impeding proliferation, invasion, and tumour growth. Phospho-proteomic, structural, and target engagement analyses, combined with in vitro, in vivo efficacy, and pharmacokinetic studies reveal that Dyr726 is a brain-penetrant small molecule which effectively reduces tumour volume and extends survival of murine orthotopic models. Our current work establishes a first-in-class brain penetrant small molecule mKI which simultaneously antagonize the PI3K-AKT-mTOR and WNT pathways in preclinical cancer stem cell cultures, adult and pediatric primary organoids, and orthotopic murine models with positive efficacy in combination with clinical standard of care.

cancer biology↗

bioRxiv2020

Tumor to normal single cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Neuroblastoma is an embryonal childhood cancer that arises from aberrant development of the neural crest, mostly within the fetal adrenal medulla. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n=16,591) with fetal adrenal single cell transcriptomes (n=57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients and clinical phenotypes. We substantiated our findings in 652 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that there exists a pan-neuroblastoma cancer cell state which may be an attractive target for novel therapeutic avenues.

cancer biology↗

bioRxiv2019

Lower dormancy with rapid germination is an important strategy for seeds in an arid zone with unpredictable rainfall

Seed germination traits are key drivers of population dynamics, yet they are under-represented in community ecology studies, which have predominately focussed on adult plant and seed morphological traits. We studied the seed traits and germination strategy of eight woody plant species to investigate regeneration strategies in the arid zone of eastern Australia. To cope with stochastic and minimal rainfall, we predict that arid seeds will either have rapid germination across a wide range of temperatures, improved germination under cooler temperatures, or dormancy and/or longevity traits to delay or stagger germination across time. To understand how temperature affects germination responses, seeds of eight keystone arid species were germinated under laboratory conditions, and under three diurnal temperatures (30/20{degrees}C, 25/15{degrees}C and 17/7{degrees}C) for 30 days. Seeds of species in this study are currently stored for minesite restoration projects, hence we tested for decline in seed viability across 24 months in dry storage at similar storage conditions ({approx}20{degrees}C). Six of the eight arid species studied had non-dormant, rapidly germinating seeds, and only two species had physiological dormancy traits. Seed longevity differed widely between species, from one recalcitrant species surviving only months in storage (P50 = <3 months) and one serotinous species surviving for many years (P50 = 84 months). Our results highlight the importance of understanding the reproductive strategies of plant species in arid environments. Rapid germination, the dominant seed trait of species included in this study, allows arid species to capitalise on sporadic rainfall. However, some species also exhibit dormancy and delayed germination; this an alternative strategy which spreads the risk of germination failure over time. We highlight important seed traits and germination strategies of plants from an arid zone with stochastic rainfall and discuss the implications for their restoration.

plant biology↗

bioRxiv2018

Maternal stress increases cooperative behaviour of offspring in wild meerkats

The phenotype of parents can have long-lasting effects on the development of offspring as well as on their behaviour, physiology, and morphology as adults. In some cases, these changes may increase offspring fitness but, in others, they can elevate parental fitness at a cost to the fitness of their offspring. We show that in Kalahari meerkats (Suricata suricatta), the circulating glucocorticoid (GC) hormones of pregnant females affect the growth and cooperative behaviour of their offspring. We performed a 3-year experiment in wild meerkats to test the hypothesis that GC-mediated maternal effects reduce the potential for offspring to reproduce directly and therefore cause them to exhibit more cooperative behaviour. Daughters (but not sons) born to mothers treated with cortisol during pregnancy grew more slowly early in life and exhibited significantly more of two types of cooperative behaviour (pup rearing and feeding) once they were adults compared to offspring from control mothers. They also had lower measures of GCs as they aged, which could explain the observed increases in cooperative behaviour. Because early life growth is a crucial determinant of fitness in female meerkats, our results indicate that GC-mediated maternal effects may reduce the fitness of offspring, but may elevate parental fitness as a consequence of increasing the cooperative behaviour of their daughters.

animal behavior and cognition↗